We have advanced the theory that a major portion of enzymatic catalysis is achieved by activation of the substrate during binding. To support the theory, we have synthesized a large variety of test-tube models which simulate the bound substrate by being frozen in a single, favorable conformation and by having the interacting functions brought into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates comparable to those catalyzed by enzymes, sometimes even too fast to measure. In recent studies, we have used long-range 19F-1H NMR coupling to assign preferred conformations to high barrier systems. The results are consistent with kinetic data for accelerated ring closure reactions. Furthermore, log k for enhanced cyclization is a function of the Van der Waals size of restricting groups and is independent of electronic effects.